The invention relates to polyethylene glycol esters of polyunsaturated fatty acids.
In many contexts polyunsaturated fatty acids are desirably made up as aqueous formulations that will be well tolerated in the body and will allow such acids to be well utilised especially in parental and topical applications. We have found that the use of polyethylene glycol esters of the fatty acids satisfies such requirements.
The invention thus provides, as nutritional, cosmetic or pharmaceutical formulations, polyethylene glycol esters in which the polyethylene glycol chain is terminated at one end by a polyunsaturated fatty acyl group preferably C18-C22 and at the other end by a straight or branched chain C1-C4 alkyl group, preferably a methyl group.
Such esters are desirably of formula.
Axe2x80x94(OCH2CH2)nxe2x80x94Oxe2x80x94A1xe2x80x83xe2x80x83(1)
where A is the polyunsaturated fatty acyl group; A1 is a straight or branched chain alkyl group as above; and n is an integer to give a molecular weight of 1,000D to 6,000D.
A variety of nutritionally or otherwise bioactive C18-C22 fatty acids with 2 to 6 unsaturations are known but the polyunsaturated fatty acids forming the present esters are preferably selected from the n-6 and n-3 essential fatty acids and most preferably the xe2x80x9cdelta 6-desaturatedxe2x80x9d acids that is to say the 18:3 n-6 and 18:4 n-3 and higher acids in the n-6 and n-3 series, particularly GLA, DGLA, AA, SA EPA and DHA. Their nomenclature and their conversions within biological systems are set out in table 1.
The acids, which in nature are of the allxe2x80x94cis configuration, are systematically named as derivatives of the corresponding octadecanoic, eicosanoic or docosanoic acids, e.g. z,z-octadeca-9,12-dienoic acid or z,z,z,z,z,z-docosa-4,7,10,13,16,19-hexaenoic acid, but numerical designations based on the number of carbon atoms, the number of centres of unsaturation and the number of carbon atoms from the end of the chain to where the unsaturation begins, such as, correspondingly, 18:2 n-6 or 22:6 n-3, are convenient. Initials, e.g. EPA, and shortened forms of the name e.g. eicosapentaenoic acid, are used as trivial names in some instances.
The preferred polyethylene glycol esters are as stated derived from the above twelve n-6 and n-3 essential fatty acids, desirably in allxe2x80x94cis form, but are not limited to them nor to acids in which the chain contains repeating xe2x80x94CHxe2x95x90CHxe2x80x94CH2xe2x80x94 units. Columbinic acid (CA) and xcex1-parinaric acids (xcex1PA) are other suitable acids and their formulae are. respectively e,z,z-octadeca-5,9,12-trienoic acid and z,e,e,z-octadeca-9,11,13,15-tetraenoic acid. A further suitable acid is xcex1-eleostearic acid.
Compounds of type (1) may be synthesized by the reaction of terminally blocked polyethers of type RH, wherein R is a straight or branched chain C1-C4 alkyl terminated polyethylene glycol chain as referred to earlier i.e. xe2x80x94(OCH2CH2)nxe2x80x94Oxe2x80x94A1, with derivatives of fatty acids e.g. of type Axe2x80x94Oxe2x80x94A or Axe2x80x94X where X is Cl or Br. The reaction may for example be carried out in a suitable solvent such as toluene or acetone at temperatures between 0xc2x0 C. and 150xc2x0 C. with or without a suitable base e.g. anhydrous potassium carbonate.
Compounds of type (1) may also be synthesized by the reaction of the polyethers, RH with fatty acids of type Axe2x80x94OH. The reaction may for example be carried out with or without a suitable solvent such as toluene or xylene in the presence of a suitable acid e.g. p-toluenesulphonic acid at temperatures between 50xc2x0 C. and 180xc2x0 C. so that the water formed is removed from the reaction e.g. by azeotropy or under vacuum.
Alternatively, the reaction may for example be carried out in a suitable solvent such as dichloromethane in the presence of a condensing agent e.g. dicyclohexylcarbodiimide and in the presence of a strong non-nucleophilic base e.g. 4-dimethylaminopyridine at temperatures between 0xc2x0 C. and 50xc2x0 C.
Compounds of type (1) may further for example be synthesized by the reaction of polyethers, RH with fatty acids of type Axe2x80x94OH or fatty acid esters of type Axe2x80x94Oxe2x80x94Y, wherein Y is defined as an alkyl group containing a 1-4 carbon atoms which may be branched, unbranched, saturated or unsaturated e.g. vinyl, in the presence of a hydrolase enzyme with or without a suitable solvent e.g. toluene at temperatures between 20xc2x0 C. and 80xc2x0 C. such that the water or alcohol formed is removed from the reaction e.g. by molecular sieves or by vacuum.
Compounds of type (1) may still further be synthesized by the reaction of the polyethers. RH with fatty acid esters of type Axe2x80x94Oxe2x80x94Y where Y is as above in the presence of a catalytic amount of an alcoholate of type M30OY 31  where Y is as above and M is an alkali or alkaline earth metal e.g. sodium. The reaction is carried out with or without a suitable solvent eg. toluene at temperatures between 50xc2x0 C. and 180xc2x0 C. such that the lower alcohol, HOxe2x80x94Y formed is removed from the reaction mixture e.g. by azeotropy or by vacuum.
The compounds of type (1) are typically from 0.5-30% particularly 5-30% and more particularly 5-20% soluble in water at 25xc2x0 C. and by analysis are shown to contain from 60-100% of the theoretical amount of fatty acyl groups. The solubility in water confers major formulation advantages on the fatty acids allowing them to be used for oral, parenteral, enteral or topical administration as solutions, emulsions, mixtures, creams, lotions or other delivery systems known to those skilled in the art.